Glucose-dependent Insulinotropic Peptide (GIP) is a 42 amino acid peptide synthesized and secreted largely from endocrine cells in the small intestine. We propose that GIP modulates bone formation and resorption in response to nutrient uptake. The documented actions of GIP imply an important role in coupling food intake and absorption in the intestine with metabolic events in a number of tissues. Our observations support a role for GIP in modulating bone cell function, since GIP receptors localize to osteoblasts, osteoblast-like cells, osteoclasts, and osteocytes. Furthermore, GIP dose dependently increases intracellular cAMP and calcium contents in the osteoblast-like cell line SaOS, and stimulates alkaline phosphatase activity, collagen synthesis, and inhibits osteoclast-induced bone resorption. Based on these in vitro findings, we propose that GIP may act as a link between the nutritional state of the organism and the balance between bone formation and resorption. To evaluate further the hypothesis that GIP is anabolic for bone, we propose to define the effects of GIP on bone mass and bone turnover in vivo, both in a genetic model of GIP overexpression in transgenic mice, and in GIP receptor knock-out mouse model. As a first test of the hypothesis, GIP receptor knock-out mice will be analyzed for bone phenotypic changes, with specific reference to bone density and bone histomorphometric indices. In addition, the role of GIP-induced inhibition of osteoclastic bone resorption in the observed increases in bone mass induced by GIP will be studied in transgenic mice overexpressing GIP. These in vivo approaches are designed to test directly whether GIP can modulate bone formation and turnover. With the establishment of a genetic system, we hope to define the role of GIP in normal bone physiology. Should the in vivo findings support the profound influence of GIP on cultured osteblastoid cells, this would establish GIP as a potential link between food intake and bone metabolism. This in turn may signal GIP as a potential hormone target for pharmacologic intervention in bone pathologies such as osteoporosis. [unreadable] [unreadable]